This proposal requests support for the Fourth Gordon Research Conference (and first associated Gordon Research Seminar) on Thiol-based Redox Regulation and signaling to be held at Bates College in Lewiston, Maine, from July 28th to August 3rd, 2012. The subtitle of this conference, "Molecular Underpinnings of Redox Regulation and Oxidative Stress," reflects the focus of the upcoming meeting on the interplay between regulation of protein function and fundamental cellular processes through redox modifications on thiols, and the dysregulation that ensues under environmental conditions that exacerbate oxidative stress. Thiol-containing proteins are major antioxidants in cells, and reversible oxidation of thiols in phosphatases, kinases and transcription factors links thiol-based redox chemistry to phosphorylation-based signaling, cell proliferation, apoptosis, gene regulation, cell cycle control and other processes and pathways. Dysregulation of thiol-based redox homeostasis, for example by exposure to environmental agents which promote the generation of excessive damaging reactive oxygen species, may impart an element of irreversibility to redox regulation and has major implications for the onset and progression of cancer and complex age-related diseases. This interdisciplinary conference is in its fourth cycle after three very successful meetings in the U.S. (2006) and Italy (2008 and 2010), and will provide, as it has in the past, an important venue for the free exchange of ideas and methodologies among the molecular biologists and toxicologists, chemists and clinicians working on various aspects of the field. While the thematic area of the conference is broad-based, its relevance to environmental stress, carcinogenesis and the molecular basis for normal human physiology and disease is enormous. By bringing together investigators with varied expertise in biophysical methods, bioinformatics and animal model systems, with clinical researchers and physicians focused on disease processes, the meeting is expected to further stimulate collaborations and catalyze scientific progress as has been exemplified by the successes of the previous meetings. Public Health Relevance: Many cellular functions rely on processes that involve changes in redox properties of particular molecules within the cell, and the dysregulation of these processes is a major component of the onset and progression of aging and cancer. One amino acid, cysteine (which contains a thiol group), serves as a molecular switch and is central to these redox changes, although very few molecular details of which redox changes occur during normal and pathological processes are known. This conference brings together chemists, molecular biologists and toxicologists, and clinicians to promote the sharing of different levels of understanding of thiol-dependent processes and enable therapeutic benefits to be gained from our improved understanding.